tbuckley/cabot-search huggingface dataset:
Prognostic Impact of Intravascular Imaging–Guided Percutaneous Coronary Intervention in Chronic Total Occlusion
Authors: David Hong, Sang Min Kim, Sang Yeub Lee, Ki Hong Choi, Young Bin Song, Jong-Young Lee, Seung-Jae Lee, Kyeong Ho Yun, Jae Young Cho, Chan Joon Kim, Hyo-Suk Ahn, Chang-Wook Nam, Hyuck-Jun Yoon, Yong Hwan Park, Wang Soo Lee, Jin-Ok Jeong, Pil Sang Song, Joon-Hyung Doh, Sang-Ho Jo, Chang-Hwan Yoon, Min Gyu Kang, Jin-Sin Koh, Kwan Yong Lee, Young-Hyo Lim, Yun-Hyeong Cho, Jin-Man Cho, Woo Jin Jang, Kook-Jin Chun, Taek Kyu Park, Jeong Hoon Yang, Seung-Hyuk Choi, Hyeon-Cheol Gwon, Joo-Yong Hahn, Joo Myung Lee
Journal: Circulation (2023)
Cell-free DNA approaches for cancer early detection and interception
Authors: Jamie E Medina, Nicholas C Dracopoli, Peter B Bach, Anna Lau, Robert B Scharpf, Gerrit A Meijer, Claus Lindbjerg Andersen, Victor E Velculescu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Rapid advancements in the area of early cancer detection have brought us closer to achieving the goals of finding cancer early enough to treat or cure it, while avoiding harms of overdiagnosis. We evaluate progress in the development of early cancer detection tests in the context of the current principles for cancer screening. We review cell-free DNA (cfDNA)-based approaches using mutations, methylation, or fragmentomes for early cancer detection. Lastly, we discuss the challenges in demonstrating clinical utility of these tests before integration into routine clinical care.
Targeting the Liver with Nucleic Acid Therapeutics for the Treatment of Systemic Diseases of Liver Origin
Authors: Anagha Gogate, Jordyn Belcourt, Milan Shah, Alicia Zongxun Wang, Alexis Frankel, Holly Kolmel, Matthew Chalon, Prajith Stephen, Aarush Kolli, Sherouk M. Tawfik, Jing Jin, Raman Bahal, Theodore P. Rasmussen, José E. Manautou, Xiao-bo Zhong
Journal: Pharmacological Reviews (2023)

Systemic diseases of liver origin (SDLO) are complex diseases in multiple organ systems, such as cardiovascular, musculoskeletal, endocrine, renal, respiratory, and sensory organ systems, caused by irregular liver metabolism and production of functional factors. Examples of such diseases discussed in this article include primary hyperoxaluria, familial hypercholesterolemia, acute hepatic porphyria, hereditary transthyretin amyloidosis, hemophilia, atherosclerotic cardiovascular diseases, alpha-1 antitrypsin deficiency-associated liver disease, and complement-mediated diseases. Nucleic acid therapeutics use nucleic acids and related compounds as therapeutic agents to alter gene expression for therapeutic purposes. The two most promising fastest-growing classes of nucleic acid therapeutics are antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). For each listed SDLO disease, this article discusses epidemiology, symptoms, genetic causes, current treatment options, and advantages and disadvantages of nucleic acid therapeutics by either ASO or siRNA drugs approved or under development. Furthermore, challenges and future perspectives on adverse drug reactions and toxicity of ASO and siRNA drugs for the treatment of SDLO diseases are also discussed. In summary, this review article will highlight the clinical advantages of nucleic acid therapeutics in targeting the liver for the treatment of SDLO diseases. <b>Significance Statement</b> SDLO diseases contain both rare and common complex diseases caused by irregular functions of the liver. Nucleic acid therapeutics have shown promising clinical advantages to treat SDLO diseases. This article aims to provide the most updated information on targeting the liver with ASO and siRNA drugs. The generated knowledge may stimulate further investigations in this growing field of new therapeutic entities for the treatment of some human systemic diseases, which currently have no or limited options for treatment.
Mutation rates and fitness consequences of mosaic chromosomal alterations in blood
Authors: Caroline J. Watson, Jamie R. Blundell
Journal: Nature Genetics (2023)

Abstract Mosaic chromosomal alterations (mCAs) are common in cancers and can arise decades before diagnosis. A quantitative understanding of the rate at which these events occur, and their functional consequences, could improve cancer risk prediction and our understanding of somatic evolution. Using mCA clone size estimates from the blood of approximately 500,000 UK Biobank participants, we estimate mutation rates and fitness consequences of acquired gain, loss and copy-neutral loss of heterozygosity events. Most mCAs have moderate to high fitness effects but occur at a low rate, being more than tenfold less common than equivalently fit single-nucleotide variants. Notable exceptions are mosaic loss of X and Y, which we estimate have roughly 1,000-fold higher mutation rates than autosomal mCAs. Although the way in which most mCAs increase in prevalence with age is consistent with constant growth rates, some mCAs exhibit different behavior, suggesting that their fitness may depend on inherited variants, extrinsic factors or distributions of fitness effects.
Molecular control of endurance training adaptation in male mouse skeletal muscle
Authors: Regula Furrer, Barbara Heim, Svenia Schmid, Sedat Dilbaz, Volkan Adak, Karl J. V. Nordström, Danilo Ritz, Stefan A. Steurer, Jörn Walter, Christoph Handschin
Journal: Nature Metabolism (2023)

Abstract Skeletal muscle has an enormous plastic potential to adapt to various external and internal perturbations. Although morphological changes in endurance-trained muscles are well described, the molecular underpinnings of training adaptation are poorly understood. We therefore aimed to elucidate the molecular signature of muscles of trained male mice and unravel the training status-dependent responses to an acute bout of exercise. Our results reveal that, even though at baseline an unexpectedly low number of genes define the trained muscle, training status substantially affects the transcriptional response to an acute challenge, both quantitatively and qualitatively, in part associated with epigenetic modifications. Finally, transiently activated factors such as the peroxisome proliferator-activated receptor-γ coactivator 1α are indispensable for normal training adaptation. Together, these results provide a molecular framework of the temporal and training status-dependent exercise response that underpins muscle plasticity in training.
Hobby engagement and mental wellbeing among people aged 65 years and older in 16 countries
Authors: Hei Wan Mak, Taiji Noguchi, Jessica K. Bone, Jacques Wels, Qian Gao, Katsunori Kondo, Tami Saito, Daisy Fancourt
Journal: Nature Medicine (2023)

Abstract Growing aging populations pose a threat to global health because of the social and psychological challenges they experience. To mitigate this, many countries promote hobby engagement to support and improve mental health. Yet, it remains unclear whether there is consistency in benefits across different national settings. We harmonized measures of hobby engagement and multiple aspects of mental wellbeing across 16 nations represented in five longitudinal studies ( N = 93,263). Prevalence of hobby engagement varied substantially across countries, from 51.0% of Spanish respondents to 96.0% of Danish respondents. Fixed effects models and multinational meta-analyses were applied to compare the longitudinal associations between hobbies and mental wellbeing. Independent of confounders, having a hobby was associated with fewer depressive symptoms (pooled coefficient = −0.10; 95% confidence intervals (CI) = −0.13, −0.07), and higher levels of self-reported health (pooled coefficient = 0.06; 95% CI = 0.03, 0.08), happiness (pooled coefficient = 0.09; 95% CI = 0.06, 0.13) and life satisfaction (pooled coefficient = 0.10; 95% CI = 0.08, 0.12). Further analyses suggested a temporal relationship. The strength of these associations, and prevalence of hobby engagement, were correlated with macrolevel factors such as life expectancy and national happiness levels but overall, little variance in findings was explained by country-level factors (&lt;9%). Given the relative universality of findings, ensuring equality in hobby engagement within and between countries should be a priority for promoting healthy aging.
The relationship between regulatory changes in cis and trans and the evolution of gene expression in humans and chimpanzees
Authors: Kenneth A. Barr, Katherine L. Rhodes, Yoav Gilad
Journal: Genome biology (2023)

Abstract Background Comparative gene expression studies in apes are fundamentally limited by the challenges associated with sampling across different tissues. Here, we used single-cell RNA sequencing of embryoid bodies to collect transcriptomic data from over 70 cell types in three humans and three chimpanzees. Results We find hundreds of genes whose regulation is conserved across cell types, as well as genes whose regulation likely evolves under directional selection in one or a handful of cell types. Using embryoid bodies from a human-chimpanzee fused cell line, we also infer the proportion of inter-species regulatory differences due to changes in cis and trans elements between the species. Using the cis / trans inference and an analysis of transcription factor binding sites, we identify dozens of transcription factors whose inter-species differences in expression are affecting expression differences between humans and chimpanzees in hundreds of target genes. Conclusions Here, we present the most comprehensive dataset of comparative gene expression from humans and chimpanzees to date, including a catalog of regulatory mechanisms associated with inter-species differences.
Control of nutrient uptake by IRF4 orchestrates innate immune memory
Authors: Endi K. Santosa, Hyunu Kim, Timo Rückert, Jean-Benoît Le Luduec, Aamna J. Abbasi, Claire K. Wingert, Lila Peters, Joe N. Frost, Katharine C. Hsu, Chiara Romagnani, Joseph C. Sun
Journal: Nature Immunology (2023)
Tumor dynamics in patients with solid tumors treated with pembrolizumab beyond disease progression
Authors: Brian G. Topp, Madhav Channavazzala, Kapil Mayawala, Dinesh P. De Alwis, Eric Rubin, Alexandra Snyder, Jedd D. Wolchok, Antoni Ribas
Journal: Cancer Cell (2023)

While many patients are treated beyond progression (TBP), the magnitude and duration of clinical benefit in these patients have not been fully quantified. Data from 799 patients with melanoma (n = 176), non-small cell lung cancer (NSCLC; n = 146), gastric cancer (GC; n = 87), head and neck squamous cell carcinoma (HNSCC; n = 112), clear-cell renal cell carcinoma (ccRCC; n = 51), and urothelial carcinoma (UC; n = 227) TBP were included. Patients had received pembrolizumab beyond confirmed progressive disease (PD) per RECIST v1.1. A subset of patients displays a 30% reduction in the sum of lesion diameters in the post-progression period (melanoma 24.4%, NSCLC 11.6%, 12.6% GC, 8.9% HNSCC, 15.7% ccRCC, and 13.2% UC). Most patients show stable target lesion dynamics in the post-progression period (melanoma, 64.8%; NSCLC, 72.6%; GC, 69.0%, 75.9% HNSCC, 72.5% ccRCC, 75.3% UC). Pembrolizumab generates meaningful efficacy in a subset of patients treated beyond RECIST v1.1 progression.
Unfolding the secrets of small cell lung cancer progression: Novel approaches and insights through rapid autopsies
Authors: Zsolt Megyesfalvi, Simon Heeke, Benjamin J. Drapkin, Anna Solta, Ildiko Kovacs, Kristiina Boettiger, Lilla Horvath, Busra Ernhofer, Janos Fillinger, Ferenc Renyi-Vamos, Clemens Aigner, Karin Schelch, Christian Lang, Gyorgy Marko-Varga, Carl M. Gay, Lauren A. Byers, Benjamin B. Morris, John V. Heymach, Peter Van Loo, Fred R. Hirsch, Balazs Dome
Journal: Cancer Cell (2023)
Laryngeal widening and adequate ventilation by expiratory pressure load training improve aerobic capacity in COPD: a randomised controlled trial
Authors: Keisuke Miki, Kazuyuki Tsujino, Motonari Fukui, Mari Miki, Takamasa Kitajima, Hitoshi Sumitani, Kazuki Hashimoto, Masashi Yokoyama, Hisako Hashimoto, Takuro Nii, Takanori Matsuki, Hiroshi Kida
Journal: Thorax (2023)

Rationale Despite strategies acting on peripheral airway obstruction in chronic obstructive pulmonary disease (COPD), exercise intolerance remains inadequately improved. We hypothesised that laryngeal narrowing is a potential treatment target of expiratory pressure load training (EPT) to improve exercise intolerance in COPD. Methods The effect of 3-month EPT was assessed in 47 patients with COPD divided into Global Initiative for Chronic Obstructive Lung Disease (GOLD) mild-to-moderate (I–II) and severe-to-very severe (III–IV), randomly allocating 1:1 to EPT or control groups. The primary outcome was endurance time in the constant work rate exercise test in GOLD III–IV patients. Results Compared with controls, EPT increased: (1) endurance time, with estimated treatment effect: +703 (95% CI: 379 to 1031) s, p=0.0008 (GOLD I–II); +390 (95% CI: 205 to 574) s, p=0.0006 (GOLD III–IV); (2) peak oxygen uptake (p=0.0086 in GOLD I–II; p=0.0004 in GOLD III–IV); (3) glottic dilatation ratio at maximum collapse on laryngoscopy in the submaximal exercise (p=0.0062 in GOLD I–II; p=0.0001 in GOLD III–IV); and (4) the inflection point of expiratory tidal volume relative to minute ventilation during the incremental exercise (p=0.0015 in GOLD I–II; p=0.0075 in GOLD III–IV). Across GOLD grades, the responses of glottic dilatation ratio at maximum collapse and the expiratory tidal volume at the inflection point were selected as more influential variables correlating with the improvement in peak oxygen uptake and endurance time, respectively. Conclusion These results show that EPT improved aerobic capacity and endurance time with larger laryngeal widening and adequate ventilation despite advanced COPD. Trial registration number UMIN000041250.
Death-seq identifies regulators of cell death and senolytic therapies
Authors: Alex Colville, Jie-Yu Liu, Cristina Rodriguez-Mateo, Samantha Thomas, Heather D. Ishak, Ronghao Zhou, Julian D.D. Klein, David W. Morgens, Armon Goshayeshi, Jayesh S. Salvi, David Yao, Kaitlyn Spees, Scott J. Dixon, Chun Liu, June-Wha Rhee, Celine Lai, Joseph C. Wu, Michael C. Bassik, Thomas A. Rando
Journal: Cell Metabolism (2023)
Masthead: (Adv. Healthcare Mater. 4/2019)
Journal: Advanced Healthcare Materials (2019)

Citizenship: Wiley's Corporate Citizenship initiative seeks to address the environmental, social, economic, and ethical challenges faced in our business and which are important to our diverse stakeholder groups.Since launching the initiative, we have focused on sharing our content with those in need, enhancing community philanthropy, reducing our carbon impact, creating global guidelines and best practices for paper use, establishing a vendor code of ethics, and engaging our colleagues and other stakeholders in our efforts.
Interferon-γ production by Tfh cells is required for CXCR3+ pre-memory B cell differentiation and subsequent lung-resident memory B cell responses
Authors: Nicole M. Arroyo-Díaz, Holly Bachus, Amber Papillion, Troy D. Randall, Jobaida Akther, Alexander F. Rosenberg, Beatriz León, André Ballesteros-Tato
Journal: Immunity (2023)
Identification of DHX40 as a candidate susceptibility gene for colorectal and hematological neoplasia
Authors: Alisa Olkinuora, Taina T. Nieminen, Suvi Douglas, Anni Kauppinen, Mika Kontro, Juho Väänänen, Matti Kankainen, Ari Ristimäki, Markus Mäkinen, Päivi Lahermo, Caroline Heckman, Janna Saarela, Milla Salonen, Anna Lepistö, Heikki Järvinen, Jukka-Pekka Mecklin, Outi Kilpivaara, Ulla Wartiovaara-Kautto, Kimmo Porkka, Päivi Peltomäki
Journal: Leukemia (2023)
Reducing the pressure in pulmonary arterial hypertension: sotatercept, haemodynamics and the right ventricle
Authors: Laura C. Price, Colm McCabe, Jason Weatherald
Journal: European Respiratory Journal (2023)

Pulmonary arterial hypertension (PAH) is a severe progressive disease characterised by obliterative vascular remodelling and increased resistance in small and medium sized pulmonary arteries. Contributing factors to PAH pathogenesis include genetic mutations including those in bone morphogenetic protein receptor type 2 (BMPR2), perivascular inflammation, systemic immune dysregulation, and imbalanced pulmonary vascular cell proliferation versus apoptosis [1]. We reflect on the crucial role for a reverse remodelling approach supported by the echo and haemodynamic data from this post hoc analysis of STELLAR.
Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial
Authors: Rogerio Souza, David B. Badesch, H. Ardeschir Ghofrani, J. Simon R. Gibbs, Mardi Gomberg-Maitland, Vallerie V. McLaughlin, Ioana R. Preston, Aaron B. Waxman, Ekkehard Grünig, Grzegorz Kopeć, Gisela Meyer, Karen M. Olsson, Stephan Rosenkranz, Jianxin Lin, Amy O. Johnson-Levonas, Janethe de Oliveira Pena, Marc Humbert, Marius M. Hoeper
Journal: European Respiratory Journal (2023)

In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH).This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate.Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm-5), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL-1·beat-1), PA compliance (0.58 mL·mmHg-1), cardiac efficiency (0.48 mL·beat-1·mmHg-1), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min-1). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg-1), end-systolic and end-diastolic RV areas (-4.39 cm2 and -5.31 cm2, respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices.In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function.
Lazertinib Versus Gefitinib Tyrosine Kinase Inhibitors in Treatment-Naíve Patients With EGFR-Mutated Advanced NSCLC: Analysis of the Asian Subpopulation in LASER301
Authors: Thanyanan Reungwetwattana, Byoung Chul Cho, Ki Hyeong Lee, Yong Kek Pang, Chin Heng Fong, Jin Hyoung Kang, Yun-Gyoo Lee, Chun Sen Lim, Pongwut Danchaivijitr, Yueh Ni Lim, Youngjoo Lee, Soon Hin How, Sarayut Geater, Sung Sook Lee, Young Joo Min, Joo-Hang Kim, Jong-Seok Lee, Gyeong-Won Lee, Ross A. Soo, Sae Young Lee, SeokYoung Choi, Myung-Ju Ahn
Journal: Journal of Thoracic Oncology (2023)

IntroductionLazertinib is a third-generation central nervous system–penetrant tyrosine kinase inhibitor targeting mutant EGFR in NSCLC. Lazertinib exhibited improved efficacy versus gefitinib in the LASER301 study; this subset analysis compared lazertinib with gefitinib among Asian patients.MethodsThe phase 3 LASER301 study evaluated lazertinib efficacy and safety in treatment-naive patients with EGFR-mutated (exon 19 deletion or L858R) locally advanced or metastatic NSCLC. Patients were randomized one-to-one and received either lazertinib or gefitinib. The primary end point was investigator-assessed progression-free survival using Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included overall survival, objective response rate, duration of response, and safety.ResultsBetween February 13, 2020, and July 29, 2022, among 258 patients of Asian descent, the median progression-free survival was significantly longer with lazertinib than gefitinib (20.6 versus 9.7 mo; hazard ratio: 0.46; 95% confidence interval [CI]: 0.34–0.63, p < 0.001), and the benefit was consistent across predefined subgroups (exon 19 deletion, L858R, baseline central nervous system metastases). Objective response rate and disease control rates were similar between treatment groups. The median duration of response was 19.4 months (95% CI: 16.6–24.9) versus 9.6 months (95% CI: 6.9–12.4) in the lazertinib versus gefitinib group. Adverse event rates in Asian patients were comparable with the overall LASER301 population. Adverse events leading to discontinuation in the lazertinib and gefitinib groups were 13% and 12%, respectively.ConclusionsIn LASER301, efficacy and safety results in Asian patients were consistent with the overall population. Lazertinib exhibited better efficacy than gefitinib in Asian patients with a tolerable safety profile.
Adverse outcomes for chronic myeloid leukemia patients with splenomegaly and low in vivo kinase inhibition on imatinib
Authors: Chung H. Kok, Verity A. Saunders, Phuong Dang, Naranie Shanmuganathan, Deborah White, Susan Branford, David Yeung, Timothy P. Hughes
Journal: Blood Cancer Journal (2023)

Abstract Variability in the molecular response to frontline tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia may be partially driven by differences in the level of kinase inhibition induced. We measured in vivo BCR::ABL1 kinase inhibition (IVKI) in circulating mononuclear cells after 7 days of therapy. In 173 patients on imatinib 600 mg/day, 23% had low IVKI (&lt;11% reduction in kinase activity from baseline); this was associated with higher rates of early molecular response (EMR) failure; lower rates of major molecular response (MMR), and MR4.5 by 36 months, compared to high IVKI patients. Low IVKI was more common (39%) in patients with large spleens (≥10 cm by palpation). Notably 55% of patients with large spleens and low IVKI experienced EMR failure whereas the EMR failure rate in patients with large spleens and high IVKI was only 12% ( p = 0.014). Furthermore, patients with large spleen and low IVKI had a higher incidence of blast crisis, inferior MMR, MR4.5, and event-free survival compared to patients with large spleen and high IVKI and remaining patients. In nilotinib-treated patients ( n = 73), only 4% had low IVKI. The combination of low IVKI and large spleen is associated with markedly inferior outcomes and interventions in this setting warrant further studies.